While the role of radiation therapy in carcinoma cervix management is undauntable for all stages. Recurrent carcinoma cervix need a lot of personalisation

1. Dr Ajeet Kumar Gandhi
MD (AIIMS); DNB; UICCF (MSKCC, USA)
Assistant professor, Radiation oncology
Dr RMLIMS, Lucknow

2. CERVICAL CANCER: SCENARIO
**Source: Globocan, 2012
 5,28,000 cases diagnosed annually worldwide with
2,66,000 deaths
 >85% of the global burden of cancers occur in
developing countries
 2nd most common cancer in India with 1,23,000
diagnosis and 67,000 deaths every year

3. Recurrent cervical cancer
 Pelvic relapse rates* in definitively treated patients: 20-40%
 Approximately 2/3rd are pelvic failures
 Approximately 80% are in the irradiated field and 20%
outside this
 Treatment is very challenging, limited options
 Limited literature and ultimate outcome is poor.
*Andreu Martinez FJ et al. Clin Transl Oncol 2005;7:323-331

4. Residual or recurrent??
How do you in your clinical practice define a
patient treated definitively with concurrent
chemoradiation followed by brachytherapy to
have:
1. Persistent disease/Recurrent disease?
2. Time point after completion of treatment for
labelling persistent disease??
3. Biopsy persistent disease??

5.  There are no definite criteria for labelling a patient to be
having persistent or recurrent disease
 Persistent/residual disease: Disease evident within 6
months of the primary treatment.
 Recurrent disease: Development of nodal or distant
metastasis 6 months after the documentation of a complete
regression of disease
*Heron CW. Clin Radiol 1988; 39:496–501

6. 45 Year, Carcinoma cervix stage IIB treated definitively
with EBRT 50.4 Gray in 28 fractions over 5.5 weeks with
concurrent Cisplatin weekly and HDR-ICRT 7 Gray in 3
fractions, now have a persistent disease at cervix,
approximately 2*2 cm (biopsy proven to be SCC) after 4
months of the completion of therapy. Metastatic work up
negative. PS (ECOG 1). Tolerated earlier treatment well.
1. Salvage surgery
2. Re-irradiation/Consolidative RT
3. Chemotherapy followed by Surgery
4. Chemotherapy
5. Observation alone

7.  1994-2001; Stage 1b1-IVA treated with CTRT
 Cervical biopsy taken 8-10 weeks after completion of
treatment
 Of 111 biopsy specimens, 21 positive for viable cells
(19%)
 Salvage surgery performed in 13/21 patients
 Patients not undergoing salvage surgery (all died of
progressive disease)

8.  1994-2011; Stage 1b1-IVA treated with CTRT
 Cervical biopsy taken 8-10 weeks after completion of
treatment
 Of 345 biopsy specimens, 84 positive for viable cells (24.3%)
 Salvage surgery performed in 61/84 patients
 Residual disease after (chemo)radiation was an independent
poor prognostic factor (hazard ratio, 3.59; 95% confidence
interval, 2.18Y5.93; P G 0.001).
 More radical surgery was not associated with improved DFS
(P = 0.81) but did result in significantly more severe
morbidity

10. Persistent/Residual disease following
definitive CTRT
1. Salvage surgery
2. Chemotherapy followed by Surgery
3. Re-irradiation/Consolidative RT
4. Chemotherapy
5. Observation alone

11. Recurrent cervical cancer:
Investigations
 Pelvic examination (if required under Anaesthesia)
 Biopsy of the recurrent local or pelvic disease??

12. Recurrent cervical cancer: Radiological
Investigations
 Contrast enhanced CT scan of abdomen and
pelvis
 Contrast enhanced MRI of the pelvis
 Whole body 18F-Fluoro-deoxy glucose PET-CT

13.  MRI superior to CT in distinguishing active disease from fibrosis
and post-treatment changes
 High signal intensity on T2W images: necrosis, inflammation,
edema etc.
 DWI and DCE images promising in distinction

14.  Imaging findings of CT and PET in 36 patients (Oct 1997-May
1998)
 They had undergone surgery and/or radiation therapy. Tumor
recurrence was confirmed by pathologic examination or follow-up
studies.
 Results:
 No significant difference in specificity (p = .2888), but significant
differences in sensitivity (p = .0339) and accuracy (p = .0244)
sensitivity specificity accuracy
PET 100% 94.4% 97.2%
CT 77.8% 83.3% 80.5%

16. Recurrent cervical cancer:
Investigations & Initial work up
 Baseline documentation with clinical diagram
 Pelvic examination (if required under Anaesthesia)
 Biopsy of the recurrent local or pelvic disease
 Chest X-Ray/CECT chest
 Cystoscopy/Sigmoidoscopy
 CECT/MRI (DWI)
 PET SCAN

17. Recurrent Cervical
Cancer
Local recurrence
•Central
•Lateral pelvic wall
•Both
•+/- Nodal
Distant
metastasis
•Para-aortic
alone
•Other sites
Local plus
distant
metastasis

18. Recurrent cervical cancer
After definitive
surgery
√
No prior
radiotherapy
After prior
radiotherapy
With or without
surgery

19. Recurrence after surgery with
no prior RT
Carcinoma cervix stage 1B1 treated with radical
surgery. No adjuvant RT given. Recurrent central
disease after 9 months of the completion of therapy.
Metastatic work up negative. PS (ECOG 1)
 Re-surgery
 EBRT and Brachytherapy
 EBRT with concurrent CT and brachytherapy
 EBRT with concurrent CT and brachytherapy f/b
Adjuvant chemotherapy

20. Recurrence after surgery with no
prior RT
 Explore surgery for very limited disease
 Usually a combination of EBRT and Brachytherapy
 Brachytherapy (Interstitial) recommended for patients
with >5 mm thickness of recurrence
 Concurrent chemotherapy* should be combined in
suitable patients
*Yu Sun Lee et al. Tumori 96:553-559;2010

21. Recurrence after prior RT
 Surgery
 Reirradiation
 Systemic therapy

22. Recurrence after prior RT:
Surgical salvage
 Patient selection criteria??
 Clinical symptoms (Unilateral leg oedema,
Sciatic pain, Hydronephrosis)
 Size and extent
 Disease free interval
 Pre-operative counselling??
 Type of surgery??

23. Surgical options
Radical hysterectomy Type 2 or 3 (Limited to cervix, <2cm,
original stage IB/IIA)
Pelvic Exenteration (if central recurrence not amenable
to radical hysterectomy and other options already exhausted)
Radical surgical resection combined with intra
operative radiotherapy (IORT) to exclude normal
tissues from the treatment
LEER (Inclusion of internal iliac vessels and
pelvic muscles)
Gadducci A, Tana R, Cosio S, Cionini L. Treatment options in recurrent cervical cancer (Review).
Oncol Lett 2010; 1:3.

24. Pre operative patient evaluation
History and Physical examination Studies
Disease free interval, stage at diagnosis CT chest, abdomen, pelvis
Symptoms of advanced disease Endorectal ultrasonography
Peripheral adenopathy Pelvic MRI
Severe COPD, limited cardiac reserve PET scanning
Nutritional state, emotional stability Hemogram , serum chemistry
Pelvic EUA Liver enzymes, serum albumin
Review histology, previous radiation
therapy and chemotherapy
Urine culture, cystoscopy, sigmoidoscopy
scopy (rigid) and colonoscopy
Enterostomal therapy consultation
Pelvic reconstruction team
Multidisciplinary oncology evaluation
Laparoscopic staging

25. Counseling
• Detailed Discussion with the patient and her family
regarding planned procedure, what will be removed,
morbidity, altered body image and sexual function.
• No guarantee of cure
• Stoma Care
• Needs for vaginal reconstruction
• Formal evaluation by psychologist
QOL
issues

26. Outcomes after Exenteration
7-35% of Exenteration performed with a curative
intent, are found to have tumor present at the
surgical resection margin after thorough
pathological evaluation.

27. 5 year overall survival was 21-
73%

28. Early (16-71%)
1. Pre operative radiation
induced tissue damage
2. Length of operation
Late (36-61%)
 Fistulae
 Obstruction

29. Recurrence after prior RT:
Reirradiation
 Patient selection criteria??
 Technique of RT??
 Radiation dose schedule and fractionation??

30. Reirradiation: Which patients??
 Site of recurrence??
 Volume of disease??
 Disease free interval??
 Histology??
 Performance status??

31. Reirradiation: Which patients??
 Central recurrences* (inoperable/unwilling for
surgery)/lateral disease
 Volume of disease**: <2-4 cm, <100 cc
 Disease free interval**
 Longer the better
 At least > 6-12 month; >2 years
 Squamous histology
 Good KPS with limited toxicities from prior RT
*Mahantshetty U. Brachytherapy 2014
**Zolciak Sivinska. Gynec Oncol 2014

32. Re-irradiation: What Technique??
 Brachytherapy (ICRT/ISBT) +/- EBRT
 Interstitial brachytherapy alone
 External beam radiotherapy (EBRT)
 IORT

35.  52 patients treated with HDR-
ISBT based Reirradiation
 Local control rate: 76%
 Grade ¾ toxicities: 25%
 Tumour size (>4 cm) and DFI (<6
months) important prognostic
factors

36.  N=50
 3 year OS and loco-regional
control: 56% and 59%
 Median RT dose=50 Gray (45-64
Gray)
 No Grade 3 or greater acute
GI/GU
 Grade 3 late toxicity <10%
 Poorer OS for DFI <2 years and
non-squamous histology (p<0.05)

37. Patients Rectum-4, Anal canal-6,
Cervix-4, Endometrium-
1, UB-1
All patients previously
treated with RT
Median previous RT
dose- 45 Gy
36 Gy/ 6 fractions in 3
weeks
Median FU- 11 months
LR- 51 %, Median DFS-
8 months
One year OS- 46%
No grade 3 acute
toxicity

38. Re-irradiation: What Technique??
 Minimize volume of irradiation: Conformal
 Avoid OARs
 Brachytherapy preferred for central, accessible site
 EBRT for very lateralized disease/para-aortic
 IORT for patients suitable for surgical salvage

39. Re-irradiation: What Technique??
 Brachytherapy (ICRT/ISBT) +/- EBRT
 Interstitial brachytherapy alone
 External beam radiotherapy (EBRT)
 IORT

40. Radiation: What doses??
 Without prior RT
 EBRT 45-50 Gray + Brachytherapy (total EQD2
65-75 Gray)
 For ReRT
 EBRT
IMRT/3DCRT: 40-50 Gray (20-25#)
SBRT: 20-36 Gray in 3-6 fractions
 Brachytherapy alone
20-25 Gray HDR in 4-5 fractions BID
 IORT: 10-30 Gray
 For palliative RT
 20-30 Gray in 5-10 fractions

41. Clinical outcome after RT
 Local control
Interstitial Brachytherapy= 25-80%
EBRT + Brachytherapy =40-80%
IORT + Surgery=20-70%
EBRT=50-60%
 3-5 year Overall survival: 30-70%

42. Morbidities and toxicities: RT
 Interstitial brachytherapy:
Grade 2 toxicities 5-10%
Earlier series: Grade 3-4 toxicities15-25%
 EBRT: Grade 3 toxicities 5-10%
 IORT + Surgery: Grade 2-3 toxicities 25-30%
(higher with higher doses)

43. Systemic therapy in
recurrent/persistent/metastatic
cervical cancers
Single agent versus combination
agents??

44.  Phase III GOG 169 study:
 N=264
 Pacli/Cis vs cisplatin
alone
 High RR (36% vs 19%)
and PFS (4.8 vs 2.8
months, p<0.001), but
no improvement in OS
 Phase III GOG 179 study:
 N=294
 Topo/Cis vs cisplatin alone
 High RR (27% vs 13%,
p=0.004) , PFS (4.6 vs 2.9
months, p=0.014), and OS (9.4
vs 6.5 months, p=0.017)

45. Combination versus single-agent
therapy
 Combination therapy was compared against single-
agent cisplatin in a 2012 meta-analysis that included five
randomized trials (n = 1114)
 Compared with combination platinum-based therapy,
single-agent cisplatin resulted in a lower ORR but was
associated with less toxicity
 Combination of cisplatin plus paclitaxel resulted in OS
ranging from 13 to 15 months and PFS from 6 to 8 months
compared to OS of 7 - 9 months and PFS of 3 months with
cisplatin alone

46. Systemic therapy in
recurrent/persistent/metastatic
cervical cancers
Single agent versus combination
agents??
Preferred combination??

47. GOG 204
 N= 434
 Randomized to cisplatin plus paclitaxel
[PC] (the reference control arm) or one
of three experimental regimens
 Cisplatin plus vinorelbine (VC)
 Cisplatin plus gemcitabine (GC)
 Cisplatin plus topotecan (TC)
 VC, GC, and TC are not superior to PC
in terms of OS
 The trend in RR, PFS, and OS favors PC

48. Systemic therapy in
recurrent/persistent/metastatic
cervical cancers
Single agent versus combination
agents??
Preferred combination??
Cisplatin or Carboplatin??

49. Cisplatin vs
Carboplatin
(JCOG0505)
• non-inferiority
of TC vs TP
• n = 250
• Primary end
point - OS
 A post-hoc analysis showed that prior
platinum exposure may impact outcomes
 Women not previously treated
with cisplatin had a lower OS when treated
with carboplatin rather than cisplatin
 Median, 13 versus 23 months; HR 0.69
 There was no statistically significant
difference among women who were
previously treated with cisplatin [HR 0.69]

50. Systemic therapy in
recurrent/persistent/metastatic
cervical cancers
Single agent versus combination
agents??
Preferred combination??
Cisplatin or Carboplatin??
Bevacizumab??

51.  GOG 240 trial
 N= 450 , 2:2 factorial design
 Randomized to chemotherapy (paclitaxel with cisplatin vs
topotecan ) with or without Bevacizumab
 A significant improvement in ORR, PFS & OS in favor of
Bevacizumab compared with chemotherapy alone
 48% vs 36%; 8 vs 6 months (HR 0.67) and 17 vs 13.3 months (HR
0.71), respectively
N Engl J Med 2014; 370:734.

54. Systemic therapy in
recurrent/persistent/metastatic
cervical cancers
 Single agent versus combination agents
 Preferred combination: Paclitaxel + Platinum
 Cisplatin or Carboplatin: Either of these
 Bevacizumab: Preferred in combination with
CT

55. Isolated Para aortic recurrence

56. Take home message!!
 Need to distinguish persistent/recurrent cervical
cancer
 Comprehensive evaluation of patient prior to treatment
 Novel imaging modalities like DWI or PET-CT may be
helpful
 Management depends on multiple factor and
multidisciplinary approach should be preferred
 Patient selection for appropriate therapy remains the
key
 Outcome remains dismal and patient counselling
regarding expected outcome and morbidities should
be always done